DESCRIPTION (Adapted from the application): The focus of this proposal is development of solid phase technology for the synthesis of combinatorial libraries of siderophore analogs. Some members of this class of compounds, such as deferoxamine, have been shown to be effective in diseases that are characterized by the presence of excess metals. By optimization of the leads generated in this program, compounds with enhanced potency and improved bioavailability may be discovered in which the toxic side effects of metal complexation associated with this class of compounds may be alleviated and oral bioavailability achieved. Metal affinity will be determined by novel high throughput screens and iron exchange and toxicity will be evaluated in vitro assays on erythrocytes and hepatocytes. Efficacy in animal models will use two different iron overload models in rats. PROPOSED COMMERCIAL APPLICATION: These studies will develop technology to speed the search for an orally available iron chelator. At present, the drug of choice for treatment of iron overload in hereditary hemochromatosis, thalassemia, and sickle cell anemia is deferoxamine. This compound must be administered by injection, has a short half-life, and is known to have toxic side effects. A new iron-chelating drug, which would be effective, non-toxic, and orally available would be welcomed in these markets.